Hydrocodone and dihydrocodeinone enol acetate are semisynthetic narcotic analgesics useful in the treatment of acute or chronic pain. Hydrocodone, dihydrocodeinone enol acetate and dihydrothebaine are important intermediates for the synthesis of other opioid narcotic analgesics, including oxycodone, dihydrocodeine, and metopon.
A variety of different chemically non-related approaches have been used for the preparation dihydrothebaine, dihydrocodeinone enol acetate, hydrocodone, and analogs thereof.
For example, dihydrothebaine was synthesized by partial reduction of thebaine (UK Pat. No. 285404; J. Am Chem. Soc (1936), 58, 1457; Helv. Chim. Acta. (1968), 51, 381) or through hydrocodone methylation processes (J. Org. Chem. (1956), 21, 370; J. Med. Chem. (1976), 19, 1171).
Further, acetylation of hydrocodone with acetic anhydride affords dihydrocodeinone enol acetate (J. Org. Chem. (1939), 3, 204; U.S. Pat. No. 1,731,152).
Hydrocodone can be prepared by reduction of codeinone (Arch. Pharm (1920), 258, 295; U.S. Pat. No. 5,571,685) or thebaine (DE Pat. No. 441,613), through isomerization of codeine in the presence of noble metal catalysts (examples may be found in “The Chemistry of the Morphine Alkaloids” by Bentley, K. W.; U.S. Pat. No. 2,544,291; U.S. Pat. No. 5,847,142, WO Pat. No. 0134608) or by Oppenauer oxidation of dihydrocodeine in the presence of aluminum alkoxides (U.S. Pat. No. 2,628,962; U.S. Pat. No. 2,654,756, U.S. Pat. No. 2,715,626).
Oppenauer oxidation of dihydrocodeine can be accomplished more conveniently in the presence of potassium tert-butoxide (U.S. Pat. No. 2,649,454; Synth. Commun. (2000), 30, 3195). Although this type of oxidation may be the method of choice for modern manufacturing, the quality of the resulting hydrocodone is unreliable due to the uncontrollable build up of process by-products, especially hydrocodone aldol dimers. Product purification, especially separation of the desired product from the dimer by-product that has properties very similar to the desired ketone product, is currently very difficult and adds multiple purification steps to the process, resulting in substantial yield loss.